Parkinson's disease (PD) is a neurological disorder characterized neuropatho-logically as a loss of dopamine neurons of the substantia nigra. This neuronal loss manifests clinically as alterations in movement, such as Bradykinesia, rigidity and/or tremor (Gelb et al., 1999, Arch. Neurol. 56: 33-39). Human genetic data have identified genes linked to the development of PD. One of these genes was localized to chromosome 6 using a cohort of juvenile onset patients and identified specifically as Parkin protein (Kitada et al., 1998, Nature 392: 605-608). Parkin protein is an E3 ligase protein that functions in the ubiquitin-proteasome pathway (UPS) (Shimura, 2000, Nature Genetics 25:302-305). The UPS is a major cellular pathway involved in the targeted removal of proteins for degradation and E3 ligases function to identify and label substrates for degradation by cellular proteasomes (Hereshko and Cienchanover, 1998, Ann. Rev. Biochem. 67; 425-479) or lysosomes (Hicke, 1999, Trends in Cell Biology 9:107-112). Ubiquitination can also serve to regulate protein function without degradation (Zhang, 2003, “Transcriptional regulation by histone ubiquitination and deubiquitination,” Genes Dev 17, 2733-40.
New therapeutic agents for treating Parkinson's disease are urgently needed. The present invention provides new methods and materials useful for identifying and validating such new therapeutic agents and for other uses.